Acute intermittent porphyria
Encyclopedia
Acute intermittent porphyria (AIP) is a rare autosomal dominant metabolic disorder
affecting the production of heme
, the oxygen-binding prosthetic group of hemoglobin
. It is characterized by a deficiency of the enzyme
porphobilinogen deaminase
. Acute intermittent porphyria is the second most common form of porphyria
(porphyria cutanea tarda
being the most common). Its incidence is estimated to be between 5 and 10 in 100,000, but this is likely underestimated because of positive cases not being induced, and long periods of latency, with an estimation that it is latent in 90% of cases.
that causes decreased amounts of the enzyme, and to a lesser degree by a mutation that causes decreased activity of each enzyme molecule.
Under normal circumstances, heme synthesis begins in the mitochondrion
, proceeds into the cytoplasm
, and finishes back in the mitochondrion. However, without porphobilinogen deaminase
, a necessary cytoplasmic enzyme, heme synthesis cannot finish, and the metabolite porphobilinogen
accumulates in the cytoplasm.
Additional factors must also be present such as hormone
s, drugs
, and dietary
changes that trigger the appearance of symptoms. Symptoms of AIP may include abdominal pain
, constipation
, and muscle weakness
.
Patients with AIP are commonly misdiagnosed with psychiatric diseases. Subsequent treatment with anti-psychotics increases the accumulation of porphrobiliogen, thus aggravating the disease enough that it may prove fatal.
(10% glucose
) infusion is recommended, which may aid in recovery. If drugs have caused the attack, discontinuing the offending substances is essential. Infection
is one of the top causes of attacks and requires vigorous treatment. Pain
is extremely severe and almost always requires the use of opiates to reduce it to tolerable levels. Pain should be treated early as medically possible due to its severity. Nausea can be severe; it may respond to phenothiazine
drugs but is sometimes intractable. Hot water baths or showers may lessen nausea temporarily, but can present a risk of burns or falls.
Hematin and heme arginate
are the drugs of choice in acute porphyria, in the United States
and the United Kingdom
, respectively. These drugs need to be given very early in an attack to be effective. Effectiveness varies among individuals. They are not curative drugs, but can shorten attacks and reduce the intensity of an attack. Side-effects are rare but can be serious. These heme
-like substances, in theory, inhibit ALA synthase and, hence, the accumulation of toxic precursors. In the United Kingdom, supplies of this drug are maintained at two national centers. In the United States, one company manufactures Panhematin for infusion. The American Porphyria Foundation has information regarding the quick procurement of the drug.
Patients with a history of acute porphyria are recommended to wear an alert bracelet or other identification at all times in case they develop severe symptoms, a result of which may be that they cannot explain to healthcare professionals about their condition and the fact that some drugs are absolutely contraindicated. An attack of acute intermittent porphyria may be precipitated by one of the "four Ms": medication, menstruation, malnutrition, maladies.
Patients that experience frequent attacks can develop chronic neuropathic pain in extremities as well as chronic pain in the gut. This is thought to be due to axonal nerve deterioration in affected areas of the nervous system. In these cases, treatment with long-acting opioids may be indicated. Some cases of chronic pain can be difficult to manage and may require treatment using multiple modalities. Depression often accompanies the disease and is best dealt with by treating the offending symptoms and, if needed, the judicious use of anti-depressants. Earl Campbell from University of Maryland performed the first successful clinical trial. Although results for this trial are still undergoing rigorous testing.
Seizures often accompany this disease. Most seizure medications exacerbate this condition. Treatment can be problematic: Barbiturates must be avoided as they commonly precipitate symptoms. Some benzodiazepines are safe, and, when used in conjunction with newer anti-seizure medications such as gabapentin
, offer a possible regimen for seizure control.
Urine
from a person experiencing an acute attack may be red or "port wine" in color because of the presence of porphyrins. In addition, urine of AIP sufferers may turn purple when exposed to ultraviolet light for a period of time.
of the artist Vincent van Gogh
is that he and his siblings, in particular his brother Theo
, suffered from AIP and syphilis. Another theorized sufferer was king George III of the United Kingdom
who even had a medallion struck to commemorate his "curing". His great-great-great-grandson Prince William of Gloucester
was reliably diagnosed with variegate porphyria in 1968.
show House
in the Season 1, finale (Episode 22), wherein House
diagnoses his ex-wife's husband with the disease.
Acute intermittent porphyria is also mentioned briefly in Season 4, Episode 4, "Guardian Angels." Porphyria is again briefly mentioned as the possible cause of "relapsing and remitting" symptoms (suggesting acute intermittent porphyria) in a patient in Season 4, Episode 6, "Whatever it Takes." Other types of porphyria also appeared on House. In season 3 episode 9, "Finding Judas", a little girl was diagnosed with Erythropoietic protoporphyria
. In season 5 episode 10, "Let Them Eat Cake", House diagnoses another patient as having Hereditary coproporphyria
. In season 7 episode 10, "Carrot or Stick", House diagnoses a father and a son with Variegate porphyria
. In season 1 episode 6, "The Socratic Method," porphyria is mentioned as a differential diagnosis for psychiatric symptoms thought to be schizophrenia.
AIP has also made two appearances on the television
show Scrubs
: in the thirteenth episode of season 4, "My Ocardial Infarction," and in the ninth episode of season 7, "My Dumb Luck
."
It later appeared in Castle: Vampire Weekend (Season 2, Episode 6), and in Grey's Anatomy: The Time Warp (Season 6, Episode 15).
Also in CSI: Crime Scene Investigators: Justice is Served (Season 1, Episode 21) aired 26 April 2001.
Series 4, episode 2 of Doc Martin also features a patient with porphyria.
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
affecting the production of heme
Heme
A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are...
, the oxygen-binding prosthetic group of hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
. It is characterized by a deficiency of the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
porphobilinogen deaminase
Porphobilinogen deaminase
Porphobilinogen deaminase is an enzyme involved in the third step of the metabolism of porphyrin, converting porphobilinogen into hydroxymethylbilane. The enzyme has the unique cofactor dipyrromethane...
. Acute intermittent porphyria is the second most common form of porphyria
Porphyria
Porphyrias are a group of inherited or acquired disorders of certain enzymes in the heme bio-synthetic pathway . They are broadly classified as acute porphyrias and cutaneous porphyrias, based on the site of the overproduction and accumulation of the porphyrins...
(porphyria cutanea tarda
Porphyria cutanea tarda
Porphyria cutanea tarda is the most common subtype of porphyria. The disorder results from low levels of the enzyme responsible for the fifth step in heme production. Heme is a vital molecule for all of the body's organs...
being the most common). Its incidence is estimated to be between 5 and 10 in 100,000, but this is likely underestimated because of positive cases not being induced, and long periods of latency, with an estimation that it is latent in 90% of cases.
Mechanism of disease
A Swedish study indicated that approximately 90% of cases of acute intermittent porphyria are due to a mutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
that causes decreased amounts of the enzyme, and to a lesser degree by a mutation that causes decreased activity of each enzyme molecule.
Under normal circumstances, heme synthesis begins in the mitochondrion
Mitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...
, proceeds into the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
, and finishes back in the mitochondrion. However, without porphobilinogen deaminase
Porphobilinogen deaminase
Porphobilinogen deaminase is an enzyme involved in the third step of the metabolism of porphyrin, converting porphobilinogen into hydroxymethylbilane. The enzyme has the unique cofactor dipyrromethane...
, a necessary cytoplasmic enzyme, heme synthesis cannot finish, and the metabolite porphobilinogen
Porphobilinogen
Porphobilinogen is a pyrrole involved in porphyrin metabolism.It is generated by aminolevulinate and the enzyme ALA dehydratase. PBG is then converted into hydroxymethyl bilane by the enzyme porphobilinogen deaminase, also known as hydroxymethylbilane synthase.Acute intermittent porphyria causes...
accumulates in the cytoplasm.
Additional factors must also be present such as hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
s, drugs
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
, and dietary
Diet (nutrition)
In nutrition, diet is the sum of food consumed by a person or other organism. Dietary habits are the habitual decisions an individual or culture makes when choosing what foods to eat. With the word diet, it is often implied the use of specific intake of nutrition for health or weight-management...
changes that trigger the appearance of symptoms. Symptoms of AIP may include abdominal pain
Abdominal pain
Abdominal pain can be one of the symptoms associated with transient disorders or serious disease. Making a definitive diagnosis of the cause of abdominal pain can be difficult, because many diseases can result in this symptom. Abdominal pain is a common problem...
, constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
, and muscle weakness
Muscle weakness
Muscle weakness or myasthenia is a lack of muscle strength. The causes are many and can be divided into conditions that have true or perceived muscle weakness...
.
Patients with AIP are commonly misdiagnosed with psychiatric diseases. Subsequent treatment with anti-psychotics increases the accumulation of porphrobiliogen, thus aggravating the disease enough that it may prove fatal.
Treatment
A high-carbohydrateCarbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
(10% glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
) infusion is recommended, which may aid in recovery. If drugs have caused the attack, discontinuing the offending substances is essential. Infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
is one of the top causes of attacks and requires vigorous treatment. Pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
is extremely severe and almost always requires the use of opiates to reduce it to tolerable levels. Pain should be treated early as medically possible due to its severity. Nausea can be severe; it may respond to phenothiazine
Phenothiazine
Phenothiazine is an organic compound that occurs in various antipsychotic and antihistaminic drugs. It has the formula S2NH. This yellow tricyclic compound is soluble in acetic acid, benzene, and ether. The compound is related to the thiazine-class of heterocyclic compounds...
drugs but is sometimes intractable. Hot water baths or showers may lessen nausea temporarily, but can present a risk of burns or falls.
Hematin and heme arginate
Heme arginate
Heme arginate is a compound of heme and arginine used in the treatment of acute porphyrias. This heme product is only available outside the United States, where the equivalent is hematin....
are the drugs of choice in acute porphyria, in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
and the United Kingdom
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
, respectively. These drugs need to be given very early in an attack to be effective. Effectiveness varies among individuals. They are not curative drugs, but can shorten attacks and reduce the intensity of an attack. Side-effects are rare but can be serious. These heme
Heme
A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are...
-like substances, in theory, inhibit ALA synthase and, hence, the accumulation of toxic precursors. In the United Kingdom, supplies of this drug are maintained at two national centers. In the United States, one company manufactures Panhematin for infusion. The American Porphyria Foundation has information regarding the quick procurement of the drug.
Patients with a history of acute porphyria are recommended to wear an alert bracelet or other identification at all times in case they develop severe symptoms, a result of which may be that they cannot explain to healthcare professionals about their condition and the fact that some drugs are absolutely contraindicated. An attack of acute intermittent porphyria may be precipitated by one of the "four Ms": medication, menstruation, malnutrition, maladies.
Patients that experience frequent attacks can develop chronic neuropathic pain in extremities as well as chronic pain in the gut. This is thought to be due to axonal nerve deterioration in affected areas of the nervous system. In these cases, treatment with long-acting opioids may be indicated. Some cases of chronic pain can be difficult to manage and may require treatment using multiple modalities. Depression often accompanies the disease and is best dealt with by treating the offending symptoms and, if needed, the judicious use of anti-depressants. Earl Campbell from University of Maryland performed the first successful clinical trial. Although results for this trial are still undergoing rigorous testing.
Seizures often accompany this disease. Most seizure medications exacerbate this condition. Treatment can be problematic: Barbiturates must be avoided as they commonly precipitate symptoms. Some benzodiazepines are safe, and, when used in conjunction with newer anti-seizure medications such as gabapentin
Gabapentin
Gabapentin is a pharmaceutical drug, specifically a GABA analogue. It was originally developed for the treatment of epilepsy, and currently is also used to relieve neuropathic pain...
, offer a possible regimen for seizure control.
Urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
from a person experiencing an acute attack may be red or "port wine" in color because of the presence of porphyrins. In addition, urine of AIP sufferers may turn purple when exposed to ultraviolet light for a period of time.
Famous sufferers
One of the many hypothesized diagnosesVincent van Gogh's medical condition
There is no consensus on Vincent van Gogh's health. His death in 1890 occurred after a self-inflicted bullet wound. Many competing hypotheses have been put forward about possible medical conditions he had...
of the artist Vincent van Gogh
Vincent van Gogh
Vincent Willem van Gogh , and used Brabant dialect in his writing; it is therefore likely that he himself pronounced his name with a Brabant accent: , with a voiced V and palatalized G and gh. In France, where much of his work was produced, it is...
is that he and his siblings, in particular his brother Theo
Theo van Gogh (art dealer)
Theodorus "Theo" van Gogh was a Dutch art dealer. He was the younger brother of Vincent van Gogh, and Theo's unfailing financial and emotional support allowed his brother to devote himself entirely to painting...
, suffered from AIP and syphilis. Another theorized sufferer was king George III of the United Kingdom
George III of the United Kingdom
George III was King of Great Britain and King of Ireland from 25 October 1760 until the union of these two countries on 1 January 1801, after which he was King of the United Kingdom of Great Britain and Ireland until his death...
who even had a medallion struck to commemorate his "curing". His great-great-great-grandson Prince William of Gloucester
Prince William of Gloucester
Prince William of Gloucester was a member of the British Royal Family, a grandson of George V.-Early life:...
was reliably diagnosed with variegate porphyria in 1968.
Cultural references
AIP makes an appearance on the televisionTelevision
Television is a telecommunication medium for transmitting and receiving moving images that can be monochrome or colored, with accompanying sound...
show House
House (TV series)
House is an American television medical drama that debuted on the Fox network on November 16, 2004. The show's central character is Dr. Gregory House , an unconventional and misanthropic medical genius who heads a team of diagnosticians at the fictional Princeton-Plainsboro Teaching Hospital in...
in the Season 1, finale (Episode 22), wherein House
Gregory House
Gregory House, M.D., or simply referred to as House, is a fictional antihero and title character of the American television series House, played by Hugh Laurie. He is the Chief of Diagnostic Medicine at the fictional Princeton-Plainsboro Teaching Hospital, where he leads a team of diagnosticians...
diagnoses his ex-wife's husband with the disease.
Acute intermittent porphyria is also mentioned briefly in Season 4, Episode 4, "Guardian Angels." Porphyria is again briefly mentioned as the possible cause of "relapsing and remitting" symptoms (suggesting acute intermittent porphyria) in a patient in Season 4, Episode 6, "Whatever it Takes." Other types of porphyria also appeared on House. In season 3 episode 9, "Finding Judas", a little girl was diagnosed with Erythropoietic protoporphyria
Erythropoietic protoporphyria
Erythropoietic protoporphyria is a relatively mild form of porphyria, although very painful, which arises from a deficiency in the enzyme ferrochelatase, leading to abnormally high levels of protoporphyrin in the tissue...
. In season 5 episode 10, "Let Them Eat Cake", House diagnoses another patient as having Hereditary coproporphyria
Hereditary coproporphyria
Hereditary coproporphyria is a type of acute porphyria that is associated with a deficiency of the enzyme coproporphyrinogen III oxidase....
. In season 7 episode 10, "Carrot or Stick", House diagnoses a father and a son with Variegate porphyria
Variegate porphyria
Variegate porphyria is an autosomal dominant porphyria that can have acute symptoms along with symptoms that affect the skin...
. In season 1 episode 6, "The Socratic Method," porphyria is mentioned as a differential diagnosis for psychiatric symptoms thought to be schizophrenia.
AIP has also made two appearances on the television
Television
Television is a telecommunication medium for transmitting and receiving moving images that can be monochrome or colored, with accompanying sound...
show Scrubs
Scrubs (TV series)
Scrubs is an American medical comedy-drama television series created in 2001 by Bill Lawrence and produced by ABC Studios. The show follows the lives of several employees of the fictional Sacred Heart, a teaching hospital. It features fast-paced screenplay, slapstick, and surreal vignettes...
: in the thirteenth episode of season 4, "My Ocardial Infarction," and in the ninth episode of season 7, "My Dumb Luck
My Dumb Luck
"My Dumb Luck" is the ninth episode of season seven and the 148th episode of the American sitcom Scrubs. It aired on April 25, 2008 on NBC- Plot :Dr. Cox is unable to diagnose a recurring patient of two years. He gives J.D...
."
It later appeared in Castle: Vampire Weekend (Season 2, Episode 6), and in Grey's Anatomy: The Time Warp (Season 6, Episode 15).
Also in CSI: Crime Scene Investigators: Justice is Served (Season 1, Episode 21) aired 26 April 2001.
Series 4, episode 2 of Doc Martin also features a patient with porphyria.
See also
- PorphyriaPorphyriaPorphyrias are a group of inherited or acquired disorders of certain enzymes in the heme bio-synthetic pathway . They are broadly classified as acute porphyrias and cutaneous porphyrias, based on the site of the overproduction and accumulation of the porphyrins...
- Pyroluria
- www.drugs-porphyria.com
- www.porphyria-europe.com